1. Field of the Invention
The present invention is broadly concerned with improved extracorporeal liver assist devices and methods designed to support a human or animal patient suffering from hepatic failure or insufficiency. More particularly, it is concerned with such an assist device designed for perfusion of the patient's blood, and wherein use is made of a semipermeable membrane supplemented with transformed hepatocytes subsequently reverted to the somatic phenotype thereof.
2. Description of the Prior Art
The progress of medical science has in recent years resulted in considerable research in the area of artificial organs. To give but one example, artificial kidney dialysis machines are now relatively commonplace, and are routinely used in cases of renal failure. In such machines, blood is withdrawn from a patient and passed through a dialysis chamber along with a dialysate; impurities within the patient's blood would normally be removed by the patient's kidneys diffused through the semipermeable membranes of the dialysis chamber, and are removed by the dialysate.
It has also been proposed in the past to provide an extracorporaeal liver assist device to support patients suffering from hepatic failure. See, for example, Wolf et al., "Bilirubin Conjunction by an Artificial Liver Composed of Cultured Cells and Synthetic Capillaries", Trans. Amer. Soc. Artif. Int. Organs (1975), pages 16-27. In the Wolf et al. procedure, hollow fiber semipermeable membrane shell and tube cartridges are employed as an artificial liver. Such devices include a plurality of elongated tubular semipermeable membrane capillaries encased within a surrounding shell. Wolf et al. made use of primary hepatocytes cultured onto the exterior surfaces of the capillary membranes to form a solid tissue mass about the capillaries which is morphologically similar to the in vivo organization of hepatocytes in normal liver. These primary hepatocytes grown on hollow fiber capillaries demonstrated the ability to perform complex functions such as bilirubin uptake conjugation and secretion which are characteristic of normal liver in situ in a living animal.
A number of other cell types have been successfully grown on hollow fiber capillaries, e.g., Chinese hamster ovary cells, monkey kidney cells, embryonic fibroblasts from chicks and mice, Chang hepatoma cells, W138 cells and virally transformed hamster embryo fibroblasts. In addition, the assumption of organ function by cells grown on hollow fiber capillaries has been investigated by Chick et al. (Science 187: 847-848 (1974); Trans. Amer. Soc. Artif. Int. Organs 21: 8-15 (1975)). This work has demonstrated the long term maintenance of pancreatic beta cells on hollow fiber capillaries and the continued production of insulin by these pancreatic beta cells for the period of in vitro culture.
The specific literature describing such prior work, as well as other literature of background interest, includes:
Knazek, R. A. (1974). Fed. Proc. Fed. Am. Soc. Exp. Biol. 33:1978-81.
Knazek, R. A.; Gullino, P. M.; Kohler, P. O; and Dedrick, R. I. (1972). Science 178:65-67.
Knazek, R. A.; Kohler, P. O.; and Gullino, P. M. (1974). Exp. Cell Res. 84:251-254.
Knisely, M. H.; Reneau, D. D.; and Bruley, D. F. (1969). Angiology 20:1-56.
Kruse, P. F.; and Miedema, E. (1965). J. Cell. Biol. 27:273.
Nettesheim, P.; and Makinodan, T. (1967). In "Methods in Developmental Biology." p. 471. Crowell-Collier, New York.
Rose, G. G. (1967). J. Cell. Biol. 32:108.
Russ, M. B. (1976). M.S. Thesis, University of Delaware, Newark.
Schratter, P. (1974). "Synthetic Capillaries for Cell Culture". Am. Lab., October:33-38.
Schratter, P. (1976). "Cell Culture With Synthetic Capillaries". Methods in Cell Biol. XIV:95
Thomlinson, R. H. and Gray, L. M. (1955). Br. J. Cancer 16:841.
Tromwell, O. A. (1958). Exp. Cell Res. 16:118-147.
White, A.; Handler, P.; and Smith, E. L. (1973). In "Principles of Biochemistry", 5th ed. p. 905. McGraw-Hill, New York.
Wolf, C. F. W. (1978). Intern. J. of Art. Organs. 1:45-51.
While liver assist devices of the type described by Wolf et al. have shown some promise, a number of very significant problems remain which have precluded the widespread use of such techniques on a clinical basis. As noted, Wolf et al. made use of primary hepatocytes. These cells will not normally divide, and therefore cannot be carried in serial subculture. As a consequence, any clinical use of a Wolf et al. liver assist device would require a continuing supply of primary hepatocytes. When it is borne in mind that such hepatocytes should preferably be taken from the same species as patient, and should moreover be histocompatible with the specific patient being treated, it will become apparent that the requirement for a continuing supply of primary hepatocytes presents a formidable if not insurmountable obstacle to repeated use of such liver assist device.
There is accordingly a decided need in the art for an improved liver assist device and method which provides needed liver function for patients suffering from hepatic failure while overcoming the practical problems associated with proposals making use of primary hepatocytes cultured onto semipermeable membranes.